Back to Search
Start Over
Thrombin receptor PAR4 drives canonical NLRP3 inflammasome signaling in the heart.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2020 Jan 07; Vol. 115 (2), pp. 10. Date of Electronic Publication: 2020 Jan 07. - Publication Year :
- 2020
-
Abstract
- The deleterious effects of diabetes in the heart are increasingly attributed to inflammatory signaling through the NLRP3 (NOD, LRR and PYD domains-containing protein 3) inflammasome. Thrombin antagonists reduce cardiac remodeling and dysfunction in diabetic mice, in part by suppressing fibrin-driven inflammation. The role of cellular thrombin receptor subtypes in this context is not known. We sought to determine the causal involvement of protease-activated receptors (PAR) in inflammatory signaling of the diabetic heart. Mice with diet-induced diabetes showed increased abundance of pro-caspase-1 and pro-interleukin (IL)-1β in the left ventricle (LV), indicating transcriptional NLRP3 inflammasome priming, and augmented cleavage of active caspase-1 and IL-1β, pointing to canonical NLRP3 inflammasome activation. Caspase-11 activation, which mediates non-canonical NLRP3 inflammasome signaling, was not augmented. Formation of the plasma membrane pore-forming protein N-terminal gasdermin D (GDSMD), a prerequisite for IL-1β secretion, was also higher in diabetic vs. control mouse LV. NLRP3, ASC and IL-18 expression did not differ between the groups, nor did expression of PAR1 or PAR2. PAR3 was nearly undetectable. LV abundance of PAR4 by contrast increased with diabetes and correlated positively with active caspase-1. Genetic deletion of PAR4 in mice prevented the diet-induced cleavage of caspase-1, IL-1β and GDSMD. Right atrial appendages from patients with type 2 diabetes also showed higher levels of PAR4, but not of PAR1 or PAR2, than non-diabetic atrial tissue, along with increased abundance of cleaved caspase-1, IL-1β and GSDMD. Human cardiac fibroblasts maintained in high glucose conditions to mimic diabetes also upregulated PAR4 mRNA and protein, and increased PAR4-dependent IL-1β transcription and secretion in response to thrombin, while PAR1 and PAR2 expressions were unaltered. In conclusion, PAR4 drives caspase-1-dependent IL-1β production through the canonical NLRP3 inflammasome pathway in the diabetic heart, providing mechanistic insights into diabetes-associated cardiac thromboinflammation. The emerging PAR4-selective antagonists may provide a feasible approach to prevent cardiac inflammation in patients with diabetes.
- Subjects :
- Aged
Animals
Caspase 1 metabolism
Cells, Cultured
Diabetes Mellitus etiology
Diabetes Mellitus genetics
Diabetes Mellitus immunology
Diabetic Cardiomyopathies etiology
Diabetic Cardiomyopathies genetics
Diabetic Cardiomyopathies immunology
Diet, High-Fat
Disease Models, Animal
Female
Fibroblasts immunology
Fibroblasts metabolism
Humans
Inflammasomes immunology
Interleukin-1beta metabolism
Intracellular Signaling Peptides and Proteins metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Myocardium immunology
Phosphate-Binding Proteins metabolism
Receptors, Thrombin deficiency
Receptors, Thrombin genetics
Signal Transduction
Diabetes Mellitus metabolism
Diabetic Cardiomyopathies metabolism
Inflammasomes metabolism
Myocardium metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Receptors, Thrombin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 31912235
- Full Text :
- https://doi.org/10.1007/s00395-019-0771-9